The present invention relates to magnetic resonance spectroscopy methods utilizing chemical shifts of hyperpolarized 129Xe.
MRI using hyperpolarized noble gases has been demonstrated as a viable imaging modality. See e.g., U.S. Pat. No. 5,545,396 to Albert et al. The contents of this patent are hereby incorporated by reference as if recited in full herein. Albert et al. proposed several techniques of introducing the hyperpolarized gas (either alone or in combination with another substance) to a subject, such as via direct injection, intravenous injection, and inhalation. See also xe2x80x9cBiological magnetic resonance imaging using laser-polarized 129Xe,xe2x80x9d Nature, pp. 199-201 (Jul. 21, 1994). Other researchers have since obtained relatively high-quality images of the lung using pulmonary ventilation of the lung with both hyperpolarized 3He and 129Xe. See J. R. MacFall et al., xe2x80x9cHuman lung air spaces: Potential for MR imaging with hyperpolarized He-3,xe2x80x9d Radiology 200, 553-558 (1996); and Mugler et al., xe2x80x9cMR Imaging and spectroscopy using hyperpolarized 129Xe gas: Preliminary human resultsxe2x80x9d Mag Res Med 37, 809-815 (1997). See also E. E. de Lange et al., xe2x80x9cLung Airspaces: MR Imaging evaluation with hyperpolarized Helium-3 gas, xe2x80x9d Radiology 210, 851-857 (1999); L. F. Donnelly et al., xe2x80x9cCystic fibrosis: combined hyperpolarized 3He-enhanced and conventional proton MR imaging in the lungxe2x80x94preliminary observations,xe2x80x9d Radiology 212, 885-889 (1999); and H. P. McAdams et al., xe2x80x9cHyperpolarized 3He-enhanced MR imaging of lung transplant recipients: Preliminary results,xe2x80x9d AJR 173, 955-959 (1999).
These researchers and others have investigated vascular and tissue imaging using inhaled or injected hyperpolarized gases to observe and detect abnormalities in body cavities. 129Xe may additionally be used to detect abnormalities within tissues because of its high solubility (relative to 3He) and lipophilic nature. Despite these advantages, hyperpolarized 129Xe cannot readily or typically achieve the signal strength readily attainable with hyperpolarized 3He. Hyperpolarized 129Xe has an inherently shorter lifespan even under the best of conditions due to depolarizing interactions between 129Xe nuclei. When hyperpolarized 129Xe additionally interacts with body tissues, its lifetime is reduced further as will be discussed hereinbelow.
129Xe can be administered to a patient by several means, such as by inhalation and injection. During inhalation delivery, a quantity of hyperpolarized 129Xe is inhaled by a subject (a subject breathes in the 129Xe gas) and the subject then holds his or her breath for a short period of time, i.e. a xe2x80x9cbreath-holdxe2x80x9d delivery. This inhaled 129Xe gas volume then exits the lung space and is generally taken up by the pulmonary vessels and associated blood or pulmonary vasculature at a rate of approximately 0.3% per second. For example, for an inhaled quantity of about 1 liter of hyperpolarized 129Xe, an estimated uptake into the body is about 3 cubic centimeters per second or a total quantity of about 40 cubic centimeters of 129Xe over about a 15 second breath-hold period. Accordingly, it has been noted that such uptake can be used to generate images of pulmonary vasculature or even organ systems more distant from the lungs. See co-pending and co-assigned U.S. patent application Ser. No. 09/271,476 to Driehuys et al, entitled xe2x80x9cMethods for Imaging Pulmonary and Cardiac Vasculature and Evaluating Blood Flow Using Dissolved Polarized 129Xe,xe2x80x9d the contents of which are hereby incorporated by reference as if recited in full herein.
Many researchers are also interested in the possibility of using inhaled 129Xe for imaging white matter perfusion in the brain, renal perfusion, and the like. While inhaled delivery 129Xe methods are suitable, and indeed, preferable, for many MR applications for several reasons such as the relatively non-invasive characteristics attendant with such a delivery to a human subject, inhalation or ventilation-based deliveries may not be the most efficient method to deliver a sufficiently large dose to more distant (away from the pulmonary vasculature) target areas of interest. In addition, due to the dilution of the inhaled 129Xe along the perfusion delivery path, relatively large quantities of the hyperpolarized 129Xe are typically inhaled in order to deliver a small fraction of the gas to the more distal target sites or organ systems. For example, the brain typically receives only about 13% of the total blood flow in the human body. Thus, the estimated 40 cc""s of hyperpolarized 129Xe taken up into the pulmonary vessels from the 1-liter inhalation dose may be reduced to only about 5 cc""s by the time it reaches the brain.
Further, the hyperpolarized state of the gas is sensitive and can decay relatively quickly due to a number of relaxation mechanisms. Indeed, the relaxation time (generally represented by a decay constant xe2x80x9cT1xe2x80x9d) of the 129Xe in the blood, absent other external depolarizing factors, is estimated at T1=4.0 seconds for venous blood and T1=6.4 seconds for arterial blood at a magnetic field strength of about 1.5 Tesla. See Wolber et al., Proc Natl Acad Sci USA 96:3664-3669 (1999). The more oxygenated arterial blood provides increased polarization life over the relatively de-oxygenated venous blood. Therefore, for about a 5-second transit time, the time estimate for the hyperpolarized 129Xe to travel to the brain from the pulmonary vessels, the 129Xe polarization is reduced to about 37% of its original value. In addition, the relaxation time of the polarized 129Xe in the lung itself is typically about 20-25 seconds due to the presence of paramagnetic oxygen. Accordingly, 129Xe taken up by the blood in the latter portion of the breath-hold cycle can decay to about 50% of the starting polarization (the polarization level of the gas at the initial portion of the breath-hold cycle). Thus, generally stated, the average polarization of the 129Xe entering the pulmonary blood can be estimated to be about 75% of the starting inhaled polarization value. Taking these scaling effects into account, the delivery to the brain of the inhaled 129Xe can be estimated as about 1.4 cc""s of the inhaled one liter dose of 129Xe polarized to the same polarization level as the inhaled gas (0.75xc3x970.37xc3x975 cc""s). This dilution reduces signal delivery efficiency; i.e. for remote target areas (such as the brain), the quantity of delivered 129Xe signal is typically severely reduced to only about 0.14% of that of the inhaled 129Xe. Since MR imaging requires high signal strength to achieve a clinically useful spatial resolution in the resulting image, inhalation delivery may not produce clinically desirable images of distal or remote target organs or regions. However, much smaller quantities, for example on the order of approximately 0.01 cc""s of 129Xe, polarized to about 10%, are sufficient to provide signal information for MR spectroscopy.
An alternative method for delivering hyperpolarized 129Xe is injection. 129Xe injection can be accomplished by suspending the hyperpolarized gas in a carrier or by direct gaseous injection. See international patent application PCT/US97/05166 to Pines et al, the contents of which are hereby incorporated by reference as if recited in full herein. In this application, Pines et al describes suitable injectable solutions in which to suspend hyperpolarized gases for in vivo use to effectively target regions or areas of the body. See also co-pending U.S. patent application Ser. No. 09/804,369 to Driehuys et al., entitled xe2x80x9cDiagnostic Procedure Using Direct Injection of Gaseous Hyperpolarized 129Xe and Associated Systems and Products,xe2x80x9d the contents of which are hereby incorporated by reference as if recited in full herein. Generally stated, this patent application describes methods and an associated apparatus for injecting hyperpolarized 129Xe directly into the vasculature. The gas is preferably delivered such that the gas substantially dissolves into the vasculature proximate to the injection site or alternatively resides in the bloodstream for a period of time. As also discussed therein, surfactants may preferably additionally be added to facilitate the dissipation of injected bubbles.
Spectroscopy using hyperpolarized 129Xe is advantageous because of the documented sensitivity of 129Xe to its environment and the comparatively low levels of hyperpolarized 129Xe signal attainable (due to both environmental factors and the inherent properties of 129Xe compared to hyperpolarized 3He). By nature, spectroscopy requires a much smaller signal density because high spatial resolution is not required. Nonetheless, important information can be garnered from hyperpolarized 129Xe spectroscopy. Many researchers have investigated characteristic chemical shifts observed when hyperpolarized 129Xe comes into contact with different tissues, as seen in Table 1. As shown, large frequency shifts (on the order of 200 parts per million or xe2x80x9cppmxe2x80x9d) from free gas phase (referenced at 0 ppm) have been observed. This frequency shift is far greater than that observed with proton spectroscopy (generally stated, at most about 5 ppm). Therefore, spectroscopy is a modality which may be particularly suited to capitalize upon the behavior of hyperpolarized 129Xe.
All of the studies tabulated above involve healthy tissues. However, because 129Xe is so sensitive to its environment, characteristics of diseased states can also be sensed with 129Xe spectroscopy. For example, Wolber et al., in xe2x80x9cIn vivo hyperpolarized 129Xe spectroscopy in tumors,xe2x80x9d Proc Int""l Mag Reson Med 8, 1440 (2000), suspended hyperpolarized 129Xe in perfluorooctyl bromide (PFOB) or saline and injected it into subcutaneous tumors grown in rats. Because Wolber et al. suspended 129Xe in a carrier fluid, the resultant signal spectrum was likely tainted or influenced by the carrier fluid. For example, the signal from the 129Xe in the saline may have substantially obscured the peak of interest (i.e. the peak reflecting the 129Xe in the tumor tissue).
However, these experiments provided very little in the way of quantifiable information. Diseases of interest often cannot be diagnosed merely by the appearance of peaks denoting characteristic chemical shifts, since healthy tissues may also exhibit the same characteristics (e.g., some lipid is expected, but an excess or reduced amount of lipid may be problematic). In view of the foregoing, there remains a need for improved methods to determine the presence of certain diseases and/or pathological conditions as well as the extent or progression of the disease or condition and/or other quantitative information.
It is therefore an object of the present invention to detect and diagnose pathological conditions in vivo utilizing characteristic chemical shifts of hyperpolarized 129Xe.
It is an additional object of the present invention to provide a method for quantifying the extent of a pathological condition.
It is a further object of the present invention to provide a method for quantification of pathological states in vivo, in a manner which can decrease the impact of certain potentially data corrupting parameters such as variations in polarization and the volume of hyperpolarized gas administered to a subject.
It is another object of the present invention to filter or suppress undesirable background information from the spectroscopic signal associated with the hyperpolarized gas, thereby providing signal characteristics associated with a physiological or pathological phenomenon of interest in vivo.
One aspect of the present invention is directed toward a method for detecting pathology using hyperpolarized 129Xe spectroscopy. This method involves administering a bolus of hyperpolarized 129Xe to a patient and transmitting an RF pulse to a region of interest. An NMR RF excitation coil positioned proximate the region of interest can be used to transmit and receive the signal(s). In addition, localizing gradients can be applied as needed in the presence of the RF pulse as is well known to those of skill in the art. The response of the hyperpolarized gas to the RF pulse is received such that spectral peaks of interest can be identified and analyzed. The spectral peak may be further evaluated or quantified, and/or normalized. A pathological condition can then be detected on the basis of comparing the spectral peaks with a standard spectrum.
In certain embodiments, the polarization of the 129Xe prior to administration as well as the volume of gas administered can be accounted for. Alternatively, the spectral peak of interest can be normalized by another selected spectral peak, such as the dissolved phase-plasma peak or dissolved phase RBC (red blood cell) peak.
In certain embodiments, where the pathological condition is a degenerative disease, the stage or progression, remission, or remedial state of the disease can be determined by taking a signal of a dose of hyperpolarized gas administered to a subject in vivo (a) at a first time and (b) at a second subsequent time (such as at selected intervals and/or before and after treatments). As such, the methods of the present invention can be used to monitor the progression of a disease and the efficacy of a treatment regimen.
In embodiments of the present invention, 129Xe signal data associated with the interaction of 129Xe and non-targeted tissues can be filtered out by employing selected RF pulse sequences. For example, NMR signals can be filtered on the basis of one or more of T1, T2, T1xcfx81, T2*, diffusion coefficient, and velocity (of the blood).
Another aspect of the present invention is directed toward a method of detecting atherosclerosis in the coronary arteries. This method involves administering a bolus of hyperpolarized 129Xe gas to a patient, delivering at least a portion of the administered hyperpolarized 129Xe gas to a region of interest, applying at least one resonant RF pulse sequence to the region of interest, acquiring and analyzing at least one NMR response signal (associated with the 129Xe), and determining the presence of atherosclerotic plaques on the basis of the analyzed response signal.
In certain embodiments, the method can also include taking a background spectrum of the heart (a spectrum of the polarized 129Xe in the blood of the chambers/vessels of the heart), which can be subtracted from the acquired signal spectra to accentuate or amplify the signal of the hyperpolarized 129Xe in the tissue (vessel wall, plaque, or other biosubstance or analyte of interest). The signal acquisitions can carried out responsive to a cardiac event and the flip angles of the excitation pulse(s) or pulse sequence(s) can be chosen such that they do not destroy all the polarization of the gas within the heart itself. Alternatively, signals of the carotid arteries may be used as indicators of the health of the coronary arteries, which can allows larger flip angles and therefore a better SNR (signal-to-noise ratio) over other regions.
Because of the comparatively low signal of 129Xe (compared to 3He) and its solubility in lipids, 129Xe spectroscopy may be particularly suitable for obtaining in vivo pathologic information on certain internal locations over 129Xe imaging. For example, because 129Xe is further sensitive to its environment, spectroscopy using 129Xe may be used as a sensitive probe for diseased states, such as evaluating in vivo an increased lipid content characteristic of arteriosclerosis or altered cells such as those characteristic of tumors, plaques or other abnormalities.
Embodiments of the present invention are therefore directed toward a method of non-invasively or minimally invasively probing tissues in vivo to detect pathological or abnormal conditions. The hypersensitivity of 129Xe to its environment, when used according to the methods of the present invention, can advantageously allow a physician or a program means to quantitatively and/or qualitatively assess the presence and/or extent of a diseased condition. The hyperpolarized gas can be administered via any desired method including, for example, inhalation and injection.